title: Lymphatic endothelial cell-secreted CXCL1 stimulates lymphangiogenesis and metastasis of gastric cancer.
abstract: Lymph node metastasis is a significant factor in gastric cancer prognosis. It is well known that cancer cells secrete lymphangiogenic factors, thereby promoting lymphangiogenesis. However, the effects of lymphatic endothelial cell (LEC)-secreted factors on the process of lymphangiogenesis and tumor cell metastasis remain unclear. We established an animal model and successfully isolated LECs from afferent lymph vessels of sentinel lymph nodes (SLNs) in animal models. A microarray analysis was performed to characterize gene expression profile in afferent LECs induced by metastatic cancer cells. There were significant differences in 846 genes between normal LECs and LECs with lymph node metastasis. Among these genes, we found that expression of CXCL1 was upregulated, which was confirmed by quantitative reverse-transcriptase polymerase chain reaction. In a coculture system, gastric cancer cells induced CXCL1 secretion from LECs, which was associated with the NF-κB pathway. CXCL1 stimulated LECs migration and tube formation involving FAK-ERK1/2-RhoA activation and reorganization of F-actin. In human gastric cancer specimens, CXCR2 expression was positively correlated with TNM (Tumor, node, metastasis) stage and lymphatic vessel density. These results suggested that LECs of afferent SLNs had specific expression profiles, which were distinct from those of normal lymphatic vessels and appeared to promote metastasis. The expression pattern described in our study, including CXCL1 in LECs and its receptor CXCR2 in cancer cells, offers a promising therapeutic target for gastric cancer.
authors.affiliation: Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Xu
authors.forename: Changhua
authors.initials: C
authors.lastname: Zhang
authors.forename: Yulong
authors.initials: Y
authors.lastname: He
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Wu
authors.initials: W
authors.lastname: Song
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Weiling
authors.initials: W
authors.lastname: He
authors.forename: Shirong
authors.initials: S
authors.lastname: Cai
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002465:Cell Movement; D002469:Cell Separation; D054360:Chemokine CXCL1 / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology; D009361:Neoplasm Invasiveness; D051381:Rats; D023063:Receptors, Interleukin-8B / Q000502:physiology; D013274:Stomach Neoplasms / Q000473:pathology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology
chemical_list: D054360:Chemokine CXCL1; D016328:NF-kappa B; D023063:Receptors, Interleukin-8B; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein